Selenium shows great promise as a chemopreventive agent for a number of different cancers including those of the prostate, colon, and lung. However, the failure of an oral selenium supplement to prevent melanoma and non-melanoma skin cancers in the Nutritional Prevention of Cancer trial of 1996 was particularly disappointing in light of the fact that skin cancer prevention was the primary goal of that trial. In the course of new studies of potential agents for prevention of melanoma, the sensitivity of melanoma cells in culture to the growth-inhibitory effects of selenium was found to be comparable to those reported for other tumor types. The work proposed in this application will test the hypothesis that melanoma is sensitive to the chemopreventive effects of selenium; that human trials which did not show those effects failed because an effective dose of selenium was not delivered to the skin, and that efficient delivery to the skin will prevent melanoma. In order to test this hypothesis, three specific aims will be performed: Aim 1: Determine the effects of selenium on melanoma cells in culture. The effects of selenium on melanoma cells in culture will be interrogated with particular emphasis on apoptosis and the unfolded protein response (UPR). These studies will solidify the molecular basis for our overall hypothesis and provide important biomarkers for the evaluation of results from the animal studies in Aim 3. Aim 2: Evaluate new formulations of Se- methylselenocysteine (SeMSec) and selenomethionine (SeMet) for the delivery of selenium to the skin of mice. Preliminary evaluations of new formulations of SeMSec and SeMet showed that they were effective at increasing total selenium in the skin of adult C57BL/6 (B6) mice. These studies will be expanded in order to identify a treatment regimen that can be used to elevate selenium in the skin of neonatal mice so that we can study the effects of selenium on melanoma in B6 mice transgenic for hepatocyte growth factor (HGF) in Aim 3. Aim 3: Evaluate the efficacy of selenoaminoacids as melanoma-preventive agents in HGF mice. HGF transgenic mice, which develop melanoma after neonatal UV irradiation, will be used to test the efficacy of new formulations of SeMSec and SeMet for the prevention of melanoma. Melanoma is a highly aggressive form of skin cancer with poor prognosis when diagnosed at later stages. The only preventive strategy identified to date is avoidance of sun exposure. Unfortunately many melanomas are thought to arise from initiating events already past such as childhood sunburn. This creates the need for agents that are effective at preventing the progression of premalignant lesions. This proposal revisits selenium as a melanoma preventive agent with an updated molecular rational and new strategy for delivery of this agent to the target organ, the skin. [unreadable] [unreadable] [unreadable]